title: Timing and dose of statin therapy define its impact on inflammatory and endothelial responses during myocardial infarction.
abstract: OBJECTIVE
  Clinical trials of statins during myocardial infarction (MI) have differed in their therapeutic regimes and generated conflicting results. This study evaluated the role of the timing and potency of statin therapy on its potential mechanisms of benefit during MI.
  
  
  RESULTS
  ST-elevation MI patients (n=125) were allocated into 5 groups: no statin; 20, 40, or 80 mg/day simvastatin starting at admission; or 80 mg/day simvastatin 48 hours after admission. After 7 days, all patients switched their treatment to 20 mg/day simvastatin for an additional 3 weeks and then underwent flow-mediated dilation in the brachial artery. As of the second day, C-reactive protein (CRP) differed between non-statin users (12.0±4.1 mg/L) and patients treated with 20 (8.5±4.0 mg/L), 40 (3.8±2.5 mg/L), and 80 mg/day (1.4±1.5 mg/L), and the daily differences remained significant until the seventh day (P<0.0001). The higher the statin dose, the lower the elevation of interleukin-2 and tumor necrosis factor-α, the greater the reduction of 8-isoprostane and low-density lipoprotein(-), and the greater the increase in nitrate/nitrite levels during the first 5 days (P<0.001). Later initiation of statin was less effective than its early introduction in relation to attenuation of CRP, interleukin-2, tumor necrosis factor-α, 8-isoprostane, and low-density lipoprotein(-), as well as in increase in nitrate/nitrite levels (P<0.0001). At the 30th day, there was no longer a difference in lipid profile or CRP between groups; the flow-mediated dilation, however, was proportional to the initial statin dose and was higher for those who started the treatment early (P=0.001).
  
  
  CONCLUSIONS
  This study demonstrates that the timing and potency of statin treatment during MI are key elements for their main mechanisms of benefit. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00906451.
authors.affiliation: Cardiology Division, Faculty of Medical Sciences, State University of Campinas, 13084-971, Campinas, Sao Paulo, Brazil. dclandrei@yahoo.com
authors.forename: Andrei C
authors.initials: AC
authors.lastname: Sposito
authors.forename: Simone N
authors.initials: SN
authors.lastname: Santos
authors.forename: Eliana Cotta
authors.initials: EC
authors.lastname: de Faria
authors.forename: Dulcineia S P
authors.initials: DS
authors.lastname: Abdalla
authors.forename: Luiza P
authors.initials: LP
authors.lastname: da Silva
authors.forename: Alexandre A Sousa
authors.initials: AA
authors.lastname: Soares
authors.forename: André V T
authors.initials: AV
authors.lastname: Japiassú
authors.forename: Jose C
authors.initials: JC
authors.lastname: Quinaglia e Silva
authors.forename: Jose A F
authors.initials: JA
authors.lastname: Ramires
authors.forename: Otavio Rizzi
authors.initials: OR
authors.lastname: Coelho
mesh_terms: D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D015415:Biomarkers / Q000097:blood; D001938:Brazil; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011446:Prospective Studies; D019821:Simvastatin / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects
chemical_list: D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D009569:Nitric Oxide; D019821:Simvastatin